This proposal is submitted as a competing renewal of R01DA11602, HIV Disease Outcomes in Drug Users in Clinical Practice. This research is based in the Johns Hopkins HIV Clinical Cohort (JHHCC), established in to investigate HIV therapeutics and disease progression in clinical practice, with a special focus on injecting drug using (IDU) and non-IDU patients. Since the introduction of HAART in the U.S., HIV infection has largely evolved into a chronic disease. HIV/AIDS research questions have also evolved as the epidemic has matured. Before HAART, our research found comparability in disease progression between IDU and non-IDU patients. We demonstrated an early reduction in AIDS and mortality among both groups after HAART was introduced. During the past 5 years, our research has shown that IDU is a significant barrier to receiving and adhering to HAART, to achieving effective viral and immunologic improvement on HAART, and to attaining the cprominent than we have seen before, i.e., liver, renal, cardiovascular and metabolic diseases, and malignancy. Long-term survival with HIV and exposure to antiretrovirals, an aging host population, and long-term use of illicit drugs may all contribute to the incidence of these comorbidities, and raises new questions about the clinical course of non-AIDS-related morbidity and mortality among IDUs and non-IDUs. Our specific aims are to, 1) Evaluate HIV disease progression among IDU and non-IDU patients as the HIV epidemic continues to mature and change in the setting of continuing advances in HAART and in the context of the clinical epidemiology of IDU, and, 2) Characterize the development and progression of non-AIDS related illnesses among IDU and non-IDU patients in the setting of longer survival, long-term antiretroviral exposure, an aging population, and in the context of relapse and remission of IDU, 3) Characterize HIV disease progression the viral hepatitis co-infected patient, d treatment for AIDS, the JHHCC is in an excellent position to identify emerging challenges for medical management of HIV infection and co-infections associated with drug addiction and the long-term consequences of HAART.